Adoptive cell transfer (ACT) therapies for melanoma patients have failed to fulfill their therapeutic promise, largely due to the transfer of short-livd and terminally differentiated cells. A lack of means for developing long- lived T cell potency has hampered ACT advancement in the clinic. Understanding and manipulating the pathways that sustain T cell memory will potentially unlock durable responses to tumors. During my time in the Paulos lab, I have found that IL-17A/IFN-?/IL-22-producing CD4+ T cells that express enzymatically active CD26 on their cell surface - termed CD4+CD26high T cells - demonstrate exquisite, durable responses to tumors compared to Th1 or Th17 cells. Further investigation revealed that these cells potentially induce the expansion and engraftment of cytotoxic CD8+ T cells in vivo. Interestingly, we found that abrogating the enzymatic activity of CD26 on CD4+CD26high T cells with Alogliptin dramatically impaired their capacity to secrete the pro-inflammatory cytokines IL-17A, IL-22, IFN-? and IL-2, as well as the cytotoxin Granzyme B. Collectively, these data suggest that the enzymatic activity of CD26 plays a critical role in the function and cytotoxicity of CD4+CD26high T cells and could augment their antitumor properties in vivo. The importance of cytokine production by CD4+ T cells on the function, proliferation and cytotoxicity of CD8+ T cells has been well studied. Based on these reports, the loss of function induced by the inhibition of CD26 enzymatic activity could potentially reduce the ability of CD4+CD26high T cells to support CD8+ T cells. Given that the combined transfer of CD4+ and CD8+ T cells has proven efficacious in ACT therapy, it's important to deduce how the enzymatic activity of CD26 on CD4+CD26high T cells affects CD8+ T cells and if this activity can be targeted for enhanced therapy. We propose to gain further insight into CD4+CD26high T cell-mediated tumor immunity, hypothesizing that the enzymatic activity of CD26 plays a crucial role in the overall activity of human CD4+CD26highT cells as well as their ability to support CD8+ T cells (Aim 1), and that targeting this novel pathway is crucial for prolonging the efficacy of cancer immunotherapy (Aim 2). Overall, the proposed research is expected to demonstrate that manipulation of the CD26 pathway may sufficiently induce durable immunity against the growth and recurrence of advanced melanoma.